Endocrine Journal 2011, 58 (11),

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1 Endocrine Journal 2011, 58 (11), Or i g i n a l An epidemiological study of the serum thyrotropin reference range and factors that influence serum thyrotropin levels in iodine sufficient areas of China Chenyan Li 1), Haixia Guan 1), Xiaochun Teng 1), Yaxin Lai 1), Yanyan Chen 2), Jiashu Yu 2), Ningna Li 2), Beibei Wang 2), Fengwei Jiang 2), Jiani Wang 2), Chenling Fan 2), Hong Wang 2), Hongmei Zhang 2), Weiping Teng 2) and Zhongyan Shan 1) 1) Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, China 2) The First Hospital of China Medical University, The Endocrine Institute of China Medical University, The Liaoning Provincial Key Laboratory of Endocrine Diseases, Shenyang, China Abstract. The aims of this study performed in 2007 were to verify the selection criteria proposed by the National Academy of Clinical Biochemistry (NACB) guidelines, to investigate factors that influence thyrotropin (TSH) levels, and to determine serum TSH reference range in iodine sufficient areas of China. After excluding 291 subjects, a total of 5,348 inhabitants from three iodine sufficient areas of Liaoning province were asked to fulfill the questionnaire, and take TSH, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) measurements and a thyroid ultrasound examination. The distribution of TSH was right skewed in normal people. It has been customary to log transform the values to observe the Gaussian distribution. In the subjects years of age, the TSH level was significantly higher than in the other age groups (p<0.001), while there were no significant difference in the TSH values of the other age groups. The TSH levels in females(1.68±1.90miu/l) were significantly higher than in males (1.45±1.92mIU/L) (p<0.001). Therefore, the normal TSH range in males over age 20 was mIU/L, and in females the range was miu/l. A family history of thyroid disease, abnormal thyroid ultrasound, a thyroid antibody-positive status were the factors that influenced the TSH reference range. Non-thyroid disease did not impact the TSH reference range significantly. We recommend use of a TSH reference range mIU/L in iodine sufficient areas of China for males and females over 20 years old. We suggest using a normal thyroid ultrasound as a new criterion in addition to the NACB guidelines to determine the TSH reference range. Key words: Thyrotropin, Normal reference range, Thyroid peroxidase antibody, Thyroglobulin antibody, Goiter Thyrotropin (TSH) is one of the main hormone produced by the anterior pituitary, and it is a sensitive indicator of hypothalamus, pituitary, and thyroid function. The subclinical thyroid disease is diagnosed by measuring serum TSH values because of the lack of specific clinical symptoms. In recent years, a number of prospective studies have reported that a significant proportion of patients with subclinical hypothyroidism develop clinical hypothyroidism several years later, and some studies have recommended that the TSH ref- Submitted Mar. 23, 2011; Accepted Aug. 22, 2011 as K11E-101 Released online in J-STAGE as advance publication Sep. 30, 2011 Correspondence to: Weiping Teng, Institute of Endocrinology,The First Affiliated Hospital of China Medical University, Shenyang , China. twpendocrine@yahoo.com.cn Zhongyan Shan, Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang , China. shanzhongyan@medmail.com.cn The Japan Endocrine Society erence range should be narrower [1, 2]. A large-scale epidemiological survey reported that greater than 95% of healthy euthyroid subjects have a serum TSH concentration <2.5μIU/mL [3]. Therefore, the recommended upper limit of TSH need to be reduce to 2.5μIU/mL[4-6]. In determining the TSH reference range, Guideline 22 of the National Academy of Clinical Biochemistry (NACB) states that, TSH reference intervals should be established from the 95% confidence limits of the logtransformed values of at least 120 rigorously screened normal euthyroid volunteers who have no family history of thyroid dysfunction, no visible or palpable goiter, and no medications (except estrogen), no detectable thyroid autoantibodies, and then log reduction [6]. Many factors could affect TSH level, and iodine is one of the main factors [7-9]. In 1996, China began to implement universal salt iodization. At present, many

2 996 Li et al. areas of China have an iodine sufficient nutrition status. However, no studies have shown whether residents have normal TSH ranges in the iodine sufficient areas. Therefore, we used the selection criteria proposed by NACB guidelines to determine the TSH reference range in iodine sufficient areas of China. Moreover, we performed an epidemiological survey to investigate factors that influence TSH. Subjects and Methods Subjects The study was performed in 2007 on a population from three iodine sufficient areas in the Liaoning province of China, including Panjin (n=2004, median urinary iodine (MUI)=261μg/L), Shenyang (n=1725, MUI =161μg/L), Zhuanghe (n=1910, MUI=145μg/L). A total of 5639 people participated in this study (age:12-85yr). The ratio of male to female was 2142:3497 (1: 1.63). The iodine nutrition status of the three areas was stable. The exclusion criteria for the study were as follows: (1)known history of thyroid disease; (2)taking medicine affecting thyroid function, such as oral contraceptives, estrogen, glucocorticoids, anti-epileptic drugs, and iodine; (3) pregnancy or breastfeeding; and (4) missing information or living in local housing for less than ten years. Sampling All subjects signed informed consent to participate in the study. Serum samples were drawn between 7:00-9:00, and all venous blood samples were obtained from the participant in the morning after an overnight fast. Blood centrifugation was performed within 30 min of drawing the blood. All serum samples were used to perform TSH, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) measurements. Serum levels of free thyroxine (FT 4 ) and free triiodothyronine (FT 3 ) were measured in subjects with abnormal serum TSH levels (less than 0.3 miu/l or greater than 4.8 miu/l). Further exclusion criteria [10] included: (1) overt hypothyroidism (TSH > 4.8 miu/l, FT 4 < 10.3 pmol/l) and (2) overt hyperthyroidism (TSH < 0.3 miu/l, FT 4 > 24.5 pmol/l, FT 3 > 6.3pmol/L). In total, 5,348 subjects were evaluated. Questionnaire The questionnaire included the participant s name, date of birth, identity card number, nationality, occupation, education, household income, smoking status, drinking history, history of thyroid disease and thyroid disease family history, use of drugs affecting thyroid function (for example: oral contraceptives, estrogen,, glucocorticoids, anti-epileptic drugs, iodine), application of iodized salt, and history and treatment for other disease, including diabetes, cardiovascular disease, cerebrovascular disease, kidney disease, cancer surgery, and other diseases described by the participants. Determination Thyroid function The chemiluminescence immunoassay kits used to measure TSH, TPOAb and TgAb were from Diagnostic Products Corporation, Los Angeles, CA, USA. The reference range for TSH was 0.3 to 4.8 miu/l. The functional sensitivity of TSH was 0.02mIU/L. The intraassay coefficients of variation (CV) ranged from 1.23% to 3.38% and interassay CV ranged from 1.2% to 4.93%. The sensitivity of the TPOAb and TgAb measurements is 10 IU/L. Serum TPOAb exceeding a level of 50 IU/L and /or TgAb exceeding a level of 40 IU/L were considered as positive [2]. Urinary iodine Urinary iodine excretion was measured in all participants, with the colorimetric ceric ion arsenious acid ash (Cs/As) method. The intra- and interassay CV were<6.7%. Thyroid Thyroid was performed by two trained observers using the same equipment. A normal thyroid ultrasound met the following criteria: 1)The echo of the thyroid gland was uniform; 2) There was no local nodule; 3) There was no goiter, The volume of the thyroid was estimated by multiplication of thickness, width, length and a corrective factor (0.479). Goiter was defined as a thyroid volume exceeding 19.4mL for women and 25.6mL for men[10]; 4) There was no significantly reduced or absence of the thyroid gland ; 5) There was no adenoma; 6) There was no calcification and acoustic halo. Statistical analysis All data were imported into an Excel table. SPSS16.0 software was used to perform the statistical analysis. The normal TSH range was determined by the 2.5%- 97.5% confidence interval, and the Kolmogorov- Smirnov method was used to test for normality. The

3 A cross-sectional study 997 Table 1 The TSH hierarchical comparison for age and gender Age group (yr) N Male Female n TSH mean % interval n TSH mean % interval (1.67) * (2.00) * (1.73) * (1.68) * (2.02) (1.62) # (1.93) (2.05) # (1.75) (1.91) # (1.74) (2.00) # (2.04) (1.83) # (1.93) (1.71) # (1.90) (1.75) # (1.68) (2.35) # Total (1.92) (1.90) # The contents in brackets represent SD. *TSH level of the and age groups were higher than other the age groups of the same sex (p<0.001). There were no statistically significant differences in the TSH levels of the other age groups (p >0.05). # The TSH levels for women over 20 years old were higher than those in men of the same age group (p <0.001). t-test was used to compare the TSH levels and logtsh values between groups. A p value < 0.05 was considered statistically significant. Results Distribution of TSH and log TSH levels The distribution of the TSH levels measured in normal subjects, who had no family history of thyroid disease, no history of any disease or drug treatment, and normal thyroid ultrasounds, and who were thyroid antibody negative, was right skewed. This distribution deviated significantly from a Gaussian distribution (p <0.001, n=2488). However, the logarithm of TSH levels were found to follow an approximately Gaussian distribution (p=0.16). Therefore, the TSH reference intervals should be log-transformed for comparison followed by a log reduction. The effects of iodine intake on TSH After correction of age and sex, the serum TSH levels of the normal subjects from the three different iodine intake areas were not statistically significantly different (p >0.05). Therefore, we incorporated the data from the three regions into one group. The effects of age and gender on TSH We stratified the normal subjects by gender and age, and found that the TSH levels of the male and female and age groups were significantly higher than in the other age groups of the same sex (compared with all other age groups, p <0.001). There was no statistically significant difference in the values of the other age groups (p >0.05). The TSH levels in women over 20 years old were higher than those in men of the same age groups (p <0.001). The upper and lower limits of the TSH normal range were both higher in women than in men (Table1). The normal range of serum TSH The range of serum TSH in the normal subjects was determined from the 2.5%-97.5% confidence interval and was miu/l (N=2488,TSH mean:1.58±1.92miu/l, age: 40.37±15.88 yr). The results indicate that gender and age (subjects younger than 20 years old) significantly affect the determination of TSH range. Thus, after excluding individuals younger than 20 years old, the 2.5%-97.5% confidence interval of serum TSH for normal people was miu/l (N=2118, TSH mean:1.49±1.91miu/l). For men, the range of serum TSH was miu/l (n=850, TSH mean:1.32±1.88 miu/l), and for women the range was miu/l (n=1268, TSH mean:1.61±1.91 miu/l). The effects of risk factors on serum TSH determination Age and gender After removing the individuals younger than 20 years old and removing the subjects who had more than two risk factors, we analyzed how single risk factor affect the TSH reference range for both men and women in the remaining 3987 subjects (Table 2).

4 998 Li et al. Table 2 Intervals of TSH in individuals with different risk factors Groups Factors N n TSH mean Male % interval p value n TSH mean Female % interval p value 1 Normal group (1.88) (1.91) Family history of thyroid disease (1.65) (1.72) * 3 Other disease (1.83) (1.86) Ultrasound abnormal (2.18) (2.42) * 5 Thyroid antibody(+) (3.84) (2.79) Only TPOAb(+) (3.88) (3.04) Only TgAb(+) (1.62) (2.44) TPOAb,TgAb both(+) (8.51) (3.18) Overall The contents in brackets represent SD. *TSH values of individuals have thyroid disease family history were higher than normal individuals in women cohort (p =0.002). TSH values of thyroid ultrasound abnormal group were lower than normal individuals in women cohort (p =0.003). TSH values was not significantly different in any group in men cohort (p >0.05). Table 3 The effects of thyroid ultrasound on level of TSH in female group Group Change of ultrasound n TSH mean p value 95% interval 1 Normal thyroid ultrasound (1.91) Diffuse goiter (2.29) * Nodular goiter (2.83) <0.001 * Hypoechoic nodular (2.05) Thyroid adenoma (2.94) Thyroid atrophy (1.94) Hyperechoic nodular (1.08) Heterogeneous abnormalities (1.71) <0.001 * The contents in brackets represent SD. *TSH level was significantly lower in the subjects with goiter,especially nodular goiter (p <0.001), than in the normal group. The TSH level was significantly in elevated in subjects with heterogeneous abnoumalities (p <0.001). Thyroid disease family history Compared with the normal population, the TSH levels were significantly higher in the study cohort of women with a family history of simple thyroid disease (p =0.002). Both the upper and lower limits of the TSH range were elevated in this group. In the males, there was no significant difference between the group with a family history of thyroid disease and the normal group (p =0.801). The upper limit of the TSH range declined (Table 2). Other disease in addition to the history of thyroid disease The TSH values were not significantly different between the group of subjects with a history of thyroid disease in addition to another disease and the normal group both in men and women (male: p =0.219, female: p =0.461). Compared with the normal group, upper and lower limits of the TSH range did not change significantly. Thyroid ultrasound abnormalities In the male and female cohorts with thyroid ultrasound abnormalities, the lower limit of the TSH range declined and the upper limit was elevated in comparison to the normal group. The changes in the TSH range were slightly larger in women with thyroid ultrasound abnormalities. In the female study cohort with thyroid ultrasound abnormalities, the average TSH level was significantly lower than in the normal group (p =0.003). Upon further analysis of the effects of thyroid ultrasound abnormality on TSH in the female cohort, we found that the TSH levels were lower when the thyroid ultrasound indicated goiter, especially the nodular goiter (p <0.001). Moreover, the TSH levels were higher when the ultrasound showed heterogeneous abnormalities, which affected both the upper and lower limits of

5 A cross-sectional study 999 TSH range (p <0.001). Thyroid adenoma did not affect the TSH values significantly, but did have some effect on the TSH range (Tables 2 and 3). Thyroid autoantibody positive In the latter four groups shown in Table 2, the TSH values were not significantly different in thyroid autoantibody positive groups (p >0.05). In females who were TPOAb-positive, here was a reduced lower limit and an elevated upper limit of the TSH range. In females who were TgAb-positive, there was an elevated upper limit of TSH range, but there was no effect on lower limit (Table 2). Discussion This epidemiological examined 5,639 individuals to determine the normal range and of serum TSH and the factors that influence TSH levels in three iodine sufficient areas of Liaoning province. In addition to the screening criteria for a normal TSH population proposed by the NACB guidelines, we added thyroid ultrasound as a screening criterion. The serum TSH for normal people determined from a 2.5%-97.5% confidence interval was miu/l. Table 4 shows the TSH range reported by researchers in various countries and regions during the last five years. The maximum and minimum of our TSH reference range is slightly higher than most international and domestic results [2, 4, 12]. Therefore, we further analyzed the factors below, which influenced normal serum TSH reference range. Age This study found that the average TSH levels of subjects younger than 20 years old were significantly higher than subjects in other age groups. The TSH levels of women in the year age group were significantly lower levels in males of the same age group. Our results also found the TSH levels were not significantly different in the groups of subjects older than age 20, which is similar to the results reported by our group in 1999 and 2004 [2]. There have been some studies on the relationship between TSH and age, but the results of those reports have been inconsistent [11-15]. We could not identify a unified conclusion about the correlation between TSH and age. Gender The study found that the TSH levels of women over 20 years of age were higher than those of men in the same age group. That is consistent with many revious reports [2, 11]. These results may indicate that TSH levels are regulated by estrogen, genetic susceptibility, environmental factors [9, 12, 15, 16]. Iodine nutritional status This study group compared the levels of serum TSH in three regions with different iodine nutritional statuses with MUI values of 83.5 μg/l (TSH: 1.15 miu/l, Table 4 Reference intervals of TSH obtained from studies of recent five years Country China (The present study) Published year Iodine status μg/L USA 2008 Not mentioned China 2008 Three areas with different iodine intakes were included, current MUI from 83.5 to 650.9μg/L Including criteria regular thyroid regular thyroid regular thyroid Method for measuring TSH Age Numbers included Reference interval ICMA ICMA ICMA Australia 2006 Iodine status NACB ICMA Germany 2005 Not mentioned regular thyroid ICMA Europe 2004 Not mentioned NACB ICMA Germany 2003 Formerly iodine dificiency, current MUI μg/ regular thyroid ICMA MUI, median urinary iodine; NACB, The National Academy of Clinical Biochemistry; ICMA, chemiluminescence immunoassay

6 1000 Li et al. reference range: miu/l), μg/l (TSH: 1.28 miu/l, reference range: miu/l), and μg/l (TSH: 1.93 miu/l, reference range: miu/l). These studies were performed separately in 1999 (n = 3761). The results showed that as the MUI increased, the upper-limit of the TSH levels and the mean TSH levels were elevated [2]. This study found little change in the iodine intake of the three regions. There were no significant differences in the TSH levels between the three regions. Other diseases The study found that common diseases (excluding the more serious chronic or malignant diseases) and conventional medicine therapy (drugs unreported to influence thyroid function) did not affect the TSH reference range in either in males or females. Compared with the normal reference population, these groups were not significantly different. This result was consistent with findings of Jensen et al. [17]. Family history We found that in the cohort of women with a family history of thyroid disease, the TSH levels were significantly high. The upper and lower reference limit were also elevated. In the group of men with a family history of thyroid disease, there was no significant difference when compared to the normal group, and the upper limit of the TSH range declined. Our interpretation for this result is that the thyroid disease susceptibility genes in females are under estrogen regulation. However, Esther s findings suggested that a family history of thyroid disease would reduce the TSH lower limit [17]. These findings differed from our results, which showed that there were different affects on the TSH range caused by family history. Because of the insufficient sample size of subjects with a family history of thyroid disease, we could not perform a specific analysis in this study. Thyroid ultrasound Abnormal thyroid ultrasound results were associated with lower TSH levels both in men and women, and these results were statistically significant in the female subjects. Compared with the normal population, the lower limit of the TSH reference range was lower and the upper limit was higher both in the men and women. The TSH reference range changed slightly in the women. Some studies have shown that the patients of autoimmune thyroid disease (AITD) with a wide range of hypoechoic thyroid showed higher TPOAb positive rate and TSH levels than in AITD patients with normal echo. The rate increased as the degree of hypoecho increased [18, 19]. Some researchers have also observed that serum TSH levels were lower in people with nontoxic diffuse and nodular goiter than normal individuals [20]. Therefore, we have analyzed whether changes in thyroid ultrasound affected the TSH level in women. The results showed that the TSH levels of patients with diffuse or nodular goiter were significantly lower than in the normal population (p =0.008, p <0.001). The TSH levels of patients with a heterogeneous echogenic pattern having thyroiditis were higher than in the normal population (p <0.001), and the upper and lower limits of TSH range both changed. The TSH levels of patients with thyroid adenoma were not significantly different from normal levels (p =0.352). However, the presence of thyroid adenoma affected the lower limit of the TSH range. That may be caused by the existence of autonomous adenoma. Therefore, given that changes in the thyroid ultrasound affect TSH levels, we recommended thyroid altrasound as a criterion when screening normal people. Thyroid autoantibodies Many studies have reported that thyroid autoantibodies affect serum TSH [19, 21, 22]. However, we believed that this relationship was not simply described by the mean TSH because we could not exclude the effects of latent thyroid disease on TSH. In the four thyroid-autoantibody-positive cohorts, the TSH levels were not significantly different in the men or women when compared to the normal population (p >0.05). TPOAb had a role in reducing the lower limit of the TSH range. TPOAb and TgAb had a role of evaluating the upper limit of TSH range. However, Jensen s et al. found that, TPOAb was involved in evaluating the upper limit of TSH range but found that TgAb reduced the the lower limit of the TSH range slightly. Many studies have shown that autoimmune thyroid disease is one of the main pathological factors affecting TSH, but the role of TgAb was uncertain. Conclusion This study demonstrated that age, gender, family history of thyroid disease, abnormal thyroid ultrasound, and thyroid autoantibodies can influence the

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